mRNA cancer vaccine discussionDr. Elias Sayour, along with Chong Zhao and Arnav Barpujari, delve into the mRNA cancer vaccine developed at the University of Florida (University of Florida)

A groundbreaking human clinical trial conducted on four adult patients at the University of Florida demonstrated the efficacy of an mRNA cancer vaccine in swiftly reprogramming the immune system to combat glioblastoma, the deadliest form of brain tumor. Published in the journal Cell on May 1, the findings mark a significant advancement in the quest for effective treatments against notoriously resistant cancers.

The findings in this human clinical trial parallel those previously observed in 10 pet dogs afflicted with naturally occurring brain tumors, whose owners consented to their participation due to the absence of alternative treatment options. Similarly, outcomes from preclinical mouse models corroborate these results. The next step involves subjecting this breakthrough to examination in a Phase 1 pediatric clinical trial targeting brain cancer.

Unlike conventional approaches, this mRNA vaccine utilizes a patient’s own tumor cells to tailor a personalized vaccine. Moreover, it incorporates a novel delivery mechanism involving lipid nanoparticles, resembling the technology employed in COVID-19 vaccines. Notably, this vaccine administers clusters of particles, akin to a “bag full of onions,” enhancing the immune system’s response compared to individual particles.

Dr. Elias Sayour, the senior author and a pediatric oncologist at UF Health, underscores the significance of this clustered delivery system in stimulating a more robust immune reaction. By educating the immune system to recognize tumors as foreign entities, this immunotherapy holds immense potential in transforming the landscape of cancer treatment.

With successful outcomes observed in adult patients, the vaccine is now poised for evaluation in a Phase 1 pediatric clinical trial targeting brain cancer. This pioneering approach heralds a new era in cancer immunotherapy, offering hope for patients grappling with aggressive malignancies.

One of the most striking revelations highlighted by Sayour, the principal investigator of the RNA Engineering Laboratory within UF’s Preston A. Wells Jr. Center for Brain Tumor Therapy, was the rapidity with which the new intravenous delivery method ignited a robust immune response to combat the tumor. “In less than 48 hours, we could see these tumors shifting from what we refer to as ‘cold’ — immune cold, very few immune cells, very silenced immune response — to ‘hot,’ very active immune response,” he explained. “That was very surprising given how quick this happened, and what that told us is we were able to activate the early part of the immune system very rapidly against these cancers, and that’s critical to unlock the later effects of the immune response.”

Glioblastoma, with a median survival of around 15 months, presents a devastating diagnosis. Current standard treatment involves surgery, radiation, and various combinations of chemotherapy.

The recent publication marks the culmination of seven years of promising translational research, beginning with preclinical mouse models and subsequently progressing to a clinical trial involving 10 pet dogs suffering from terminal brain cancer with no alternative treatment options. This trial, conducted with the owners’ consent in collaboration with the UF College of Veterinary Medicine, utilized dogs as a naturally occurring model for malignant glioma. Sheila Carrera-Justiz, a veterinary neurologist at the UF College of Veterinary Medicine partnering with Sayour on the clinical trials, emphasized the significance of this approach, noting that gliomas in dogs are uniformly fatal.

Following successful personalized mRNA vaccine treatments administered to pet dogs with spontaneous brain cancer, Sayour’s team transitioned to a small Food and Drug Administration-approved clinical trial aimed at assessing safety and feasibility before scaling up to a larger trial.

In this trial involving four patients, RNA extracted from each patient’s own surgically removed tumor was used to amplify messenger RNA (mRNA) — the genetic blueprint found in every cell, including tumor cells. This mRNA was then encapsulated in biocompatible lipid nanoparticles, creating a high-tech packaging that mimicked the appearance of a dangerous virus when reintroduced into the bloodstream, thereby triggering an immune response. The vaccine was tailored to each patient to leverage their unique immune system.

Duane Mitchell, director of the UF Clinical and Translational Science Institute and the UF Brain Tumor Immunotherapy Program, and a co-author of the paper, emphasized the significance of these findings, particularly in demonstrating consistent and robust immune responses across different species. He underscored the novelty of this mRNA delivery approach in generating rapid and substantial immune responses observed in both animal models and human patients, highlighting its potential impact beyond the realm of COVID-19 vaccines.

Although it’s too early in the trial to gauge the clinical impacts of the vaccine, patients either experienced prolonged periods free of disease or outlived initial prognostications.

The 10 canine participants exhibited a median survival of 139 days, notably surpassing the typical survival range of 30 to 60 days for dogs afflicted with the same condition.

The subsequent phase, backed by support from the US Food and Drug Administration and the CureSearch for Children’s Cancer foundation, entails an expanded Phase I clinical trial aiming to include up to 24 adult and pediatric patients to authenticate the initial findings. Following the confirmation of an optimal and safe dosage, an estimated 25 children are expected to partake in Phase 2, according to Sayour, an associate professor in the Lillian S. Wells Department of Neurosurgery and the department of pediatrics within the UF College of Medicine at UF Health.

For this forthcoming clinical endeavor, Sayour’s laboratory will collaborate with the Pediatric Neuro-Oncology Consortium, a multi-institutional consortium, to distribute the immunotherapy treatment to children’s hospitals nationwide. The process involves acquiring an individual patient’s tumor, manufacturing the personalized vaccine at UF, and dispatching it back to the patient’s medical team, as explained by Sayour, who also co-leads the Immuno-Oncology and Microbiome research program at the UF Health Cancer Center.

Despite the promising outcomes, the authors acknowledge a key limitation concerning the ongoing uncertainty surrounding the optimization of immune system manipulation while mitigating potential adverse effects.

“I am optimistic that this could mark a new era in patient treatment, a novel platform technology for immune system modulation,” remarked Sayour, who holds the Stop Children’s Cancer/Bonnie R. Freeman Professorship for Pediatric Oncology Research. “I am hopeful that this could synergize with other immunotherapies and perhaps unlock their potential. Our paper demonstrated the potential synergy with other immunotherapy modalities, paving the way for combination approaches.”